The present invention relates to methods and apparatus for treatment of Parkinson""s disease.
Parkinson""s disease (PD) is one of the most common neuro-degenerative diseases which affect the elderly.
The following is a representative list of references which discuss Parkinson""s disease and therapeutic strategies:
1. de Rijk M C, Breteler M M B, Graveland G A, et al. Prevalence of Parkinson""s disease in the elderly: The Rotterdam study. Neurol. 1995; 45:2143-2146.
2. Bennet D A, Beckett L A, Murray A M, et al. Prevalence of Parkinsonian signs and associated mortality in a community population of older people. N Engl. J. Med. 1996; 334(2):71-76.
3. Hornykiewicz O, Kish S J. Biochemical pathophysiology of Parkinson""s disease. Adv Neurol. 1986; 45:19-34.
4. Leenders K L, Salmon E P, Tyrrel P, et al. The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson""s disease. Arch Neurol. 1990; 47:1290-1298.
5. LeWitt P A. Levodopa Therapeutics: New treatment strategies. Neurology 1993; 43(suppl. 6):S31-S37.
6. Peppe A, Dambrosia J M, Chase T N. Risk factors for motor response complications in L-Dopa treated parkinsonian patients. Adv Neurol 1993; 60:698-702.
7. Chase T N, Mouradian M M, Engber T M. Motor response complications and the function of striatal efferent systems. Neurology 1993; 43(suppl. 6): S23-S27.
8. Doller H J, Connor J D. Changes in neostriatal dopamine concentrations in response to levodopa infusions. J Neurochem 1980; 34:1264-1269.
9. Spencer S E, Wooten G F. Altered pharmacokinetics of L-dopa metabolism in rat striatum deprived of dopaminergic innervation. Neurology 1984; 34:1105-1108.
10. Spencer S E, Wooten G F. Phariacologic effects of L-dopa are not closely linked temporally to striatal dopamine concentration. Neurology 1984; 34:1609-1611.
11. Hardie R J, Malcolm S L, Lees A J, et al. The pharmacokinetics of intravenous and oral levodopa in Parkinson""s patients who exhibit on-off fluctuations Br J Clin Pharmacol 1986; 22:421-436.
12. Fabbrini G, Juncos J, Mouradian M M, et al. Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson""s disease. Ann Neurol 1987; 21:370-376.
13. Nutt J G, Woodward W R, Hammerstad J P, et al. The xe2x80x9con-offxe2x80x9d phenomenon in Parkinson""s disease: relation to levodopa absorption and transport. N Engl J Med 1984; 310:483-488.
14. Shoulson I, Glaubiger G A, Chase T N. On-off response: clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients. Neurology 1975; 25:1144-1148.
15. Quinn N, Parkes J D, Marsden C D. Control of on/off phenomenon by continuous intravenous infusion of levodopa. Neurology 1984; 34:1131-1136.
16. Schuh L A, Bennet J P. Suppression of dyskinesias in advanced Parkinson""s disease. I. Continuous intravenous levodopa shifts dose-response for production of dyskinesias but not for relief of parkinsonism in patients with advanced Parkinson""s disease. Neurology 1993; 43:1545-1550.
17. Sage J I, McHale D M, Sonsulla P, et al. Continuous levodopa in fusion to treat complex dystonia in Parkinson""s disease. Neurology 1989; 39:888-891.
18. Schelosky L, Poewe W. Current strategies in the drug treatment of advanced Parkinson""s diseasexe2x80x94new modes of dopamine substitution. Acta neurol Scand 1993; 87(suppl. 146):46-49.
19. Nutt J G, Woodward W R. Levodopa pharmacokinetics and pharmacodynamics in fluctuating parkinsonian patients. Neurology 1986; 36:739-744.
20. Nelson M V, Berchou R C, LeWitt P A, et al. Pharmacodynamic modeling of concentration-effect relationship after controlled-release carbidopa/levodopa (Sinemet CR-4) in Parkinson""s disease. Neurology 1990; 40:70-74.
21. Bredberg E, Nilson D, Johansson K, et al. Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in sever Parkinson""s disease. Eur J Clin Pharmacol 1993; 45:117-122.
22. Mouradian M M, Juncos J L, Fabbrini G, et al. Motor fluctuations in Parkinson""s disease: central pathophysiological mechanisms. Part II. Ann Neurol 1988; 24;372-378.
23. Sage J I Mark M H. The rationale for continuous dopaminergic stimulation in patients with Parkinson""s disease. Neurology 1992; 42(Suppl. 1):23-28.
24. Chase T N, Baronti F. Fabbrini G, et al. Rational for continuous dopaminometic therapy of Parkinson""s disease. Neurology 1989; 39(Suppl. 2):7-10.
25. Sage J I, Mark M H. Basic mechanisms of motor fluctuations. Neurology 1994; 44(Suppl. 6):S10-S14.
26. Sage J L, Trooskin S, Sonsalla P K, et al. Experience with continuous enteral levodopa infusions in the treatment of 9 patients with advanced Parkinson""s disease. Neurology 1989; 39(Suppl. 2):60-63.
27. Mouradian M M, Heuser I J E, Baronti F, et al. Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson""s disease. Ann Neurol 1990; 27:18-23.
28. Bravi D, Mouradian M M, Roberts J W, et al. End-of-dose dystonia in Parkinson""s disease. Neurology 1993; 43:2130-2131.
29. Tanner C M, Melamed E, Lees A J. Managing motor fluctuations, dyskinesias and other adverse effects in Parkinson""s disease. Neurology 1994; 44(Suppl. 1):S12-S16.
30. Joseph King Ching Tsui. Future Treatment of Parkinson""s disease. Can J Neurol Science 1992; 19:160-162.
31. Djaldetti R, Atlas D, Melamed E. Subcutaneous injections of levodopa-ethylester: A potential novel rescue therapy for response fluctuations in patients with Parkinson""s disease (Abst). Neurology 1995; 45(Suppl. 4):415S.
32. LeWitt P A. In: Levodopa controlled-release preparations. Neurology 1993; 43(Suppl. 6)S38-S40.
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The prevalence of diagnosed PD in the population above the age of 55 is about 1.4% and it increases with age (Ref. 1). Moreover, Parkinsonian signs in the elderly are estimated to occur in 30% of the population over the age of 65 (Ref. 2). Although PD is considered a multisystem disease, it is mainly a movement disorder caused by a continuous, long lasting degeneration of the dopaminergic neurons that are located in the mesencephalic substantia nigra pars compacta. PD becomes symptomatic only after degeneration of about 60-80% of these dopaminergic neurons, or after the loss of about 90% of the striatal dopamine (Refs. 3, 4). Dopamine (DA), which is produced within the substantia nigra, reaches the striatum via the nigro-striatal tract and is released at the striatal synapses. DA deficiency in the striatum, due to the degeneration of the dopaminergic neurons in the substantia nigra, is considered to be the cause of PD. Consequently, the most effective treatment of PD is Levodopa (LD), which is converted to DA by enzymatic decarboxylation. Inhibition of the peripheral aromatic amino acid decarboxylase by carbidopa (an inhibitor that cannot penetrate the blood-brain-barrier) improves dramatically the results of the treatment. However, the currently available LD preparations are effective only for a relatively short period and may be even deleterious, under certain conditions (as will be explained below).
Administration of LD is especially successful during early stages of the disease. Adverse effects of LD, such as dyskinesias and hallucinations that occur at early stages of the disease are dose-dependent. These adverse effects are attributed to hypersensitivity of denervated striatal dopaminergic receptors to exogenous dopamine (Ref. 5). At late stages of the disease additional types of adverse effects appear as the response to LD becomes unpredictable, fluctuative and the duration of the response is reduced. Motor fluctuations appear after about 4-5 years from the introduction of LD therapy in 24%-84% of the patients (Ref. 6). The most common and disabling motor complications are: 1) xe2x80x9cwearing-offxe2x80x9d fluctuations; 2) xe2x80x9con-offxe2x80x9d fluctuations and 3) peak-dose dyskinesias (Ref. 7).
The xe2x80x9cwearing-offxe2x80x9d effect means a reduction in the duration of the beneficial effect after each administration of LD. During this period, LD must be administered more frequently than before, a problem which severely affects the quality of life of the patient. Complications such as xe2x80x9cwearing offxe2x80x9d may arise due to limitation of storage capacity of DA in the CNS (Refs. 5, 8-10). When neuronal DA storage is reduced, the clinical state of the patients becomes fully dependent on the fluctuating blood level of LD. Since the normal half-life of LD in the circulation is 1-2 hours (Refs. 11-13), LD should be administered at this stage more frequently and the effect is fluctuative. Moreover, with the currently available oral preparations, the blood level of LD is a function of the rate of absorption from the gastro-intestinal tract, which is irregular and uncontrollable. The resulting fluctuations of the LD blood levels contribute further to the instability of the effect. A continuous drug delivery, which maintains a constant blood level of LD, has been shown to improve significantly the clinical state of the fluctuating parkinsonian patients (Refs. 13-18). In this regard, it has been reported that therapeutic effects of LD were noticed when LD plasma levels reached 300-800 ng/ml (Refs. 19-21).
The xe2x80x9con-offxe2x80x9d fluctuations are inconsistent transitions between a hypokinetic parkinsonian state (the xe2x80x9coffxe2x80x9d state) and a hyperkinetic state (the xe2x80x9conxe2x80x9d state). The clinical state of these patients is highly correlated with the plasma concentration of LD (Refs. 5, 20). It is thought that these fluctuations result from a narrowing of the therapeutic window of LD. An intermittent administration of LD, given for a long period, is considered to be one of the major causes of the reduction of the therapeutic window (Refs. 22, 23) and consequently leads to the motor fluctuations (Refs. 23-25). On the other hand, a continuous infusion of LD has been shown to increase the therapeutic window and to reduce the xe2x80x9con-offxe2x80x9d fluctuations (Refs. 25-27). Moreover, during a continuous administration, the blood levels of LD which are needed to keep the patient at the xe2x80x9conxe2x80x9d state gradually decrease (Ref. 21).
Peak-dose dyskinesia is a common advanced motor complication which occurs when the blood level of LD rises to its peak. This complication is observed in advanced stages of the disease when patients show a very steep dose-response curve. Under such circumstances, small shifts in circulating LD levels, and thus in cerebral DA, induce major swings in the clinical state (Ref. 7). In this stage of the disease, a continuous administration that keeps the circulating LD level constant, may prevent the dyskinesias. Moreover, these kinds of dyskinesias, like the xe2x80x9con-offxe2x80x9d dyskinesia, may not develop during a continuous administration of LD (Refs. 7, 16, 17, 28, 29).
All these findings and observations clearly suggest that a continuous delivery of LD is advantageous over an intermittent administration. Persistent attempts have been made in effort to develop a sustained delivery of LD (Refs. 30, 31). Strategies to improve the clinical results of intermittent LD administration include controlled release (CR) preparations and pump-delivery of LD. However, the existing preparations and devices suffer from several disadvantages as follows:
1. CR preparations have a delayed onset. The peak effect of Sinemet CR (commercially available from Merck Sharp and Dohme Research Laboratories) was shown to occur an hour later than that of the conventional Sinemet (Refs. 18, 32).
2. The bioavailability of the CR preparations is low (Refs. 18, 32). The low bioavailability is explained by the variable properties of the gastro-intestinal tracts (Ref. 33).
3. Reduced reliability and predictability of the clinical response (Refs. 32, 33).
4. According to many investigators, the CR preparations do not provide the same favorable effect which was demonstrated by a continuous administration of LD such as an IV infusion (e.g., Refs. 5, 15, 18).
5. Sclerosis of the peripheral veins occurs frequently during an IV infusion of LD (Ref. 5).
6. A gastrostom-duodenal tube or an esophageal catheter is very unpleasant.
To overcome these disadvantages, and yet to administer LD in a continuous manner, an alternative method of drug delivery is needed.
In the present invention, we claim that transdermal delivery of LD could be the best substitution for the methods of continuous invasive infusions, free of disadvantages of the currently available strategies.
The present invention constitutes a solution to most of the problems associated with the currently available treatments, and thus provides a safer and more effective treatment for PD.
The invention describes a novel route of administration of levodopa dissolved in a formulation which is designed to maintain stability of the drug in solution and enables continuous penetration of the drug through the skin. This method is suggested as a treatment of Parkinson""s patients, especially at advanced stages of the disease. The currently available LD preparations cause side effects and deterioration in the clinical state of the disease. The present invention helps overcome these disadvantages.
In accordance with a preferred embodiment of the present invention, an alkyl-ester of LD such as levodopa-ethyl-ester (LDEE) is administered transdermally. For this purpose, the alkyl-ester of LD is dissolved in an appropriate formulation. The formulation consists of propylene glycol, a fatty acid and a detergent. The LD-alkyl-ester and the formulation (the solvent) are kept separately and mixed just before the beginning of the drug application. A transdermal device which includes a container connected to a patch via a narrow plastic tube is used for the transdermal delivery. The container is refilled every 24 h. The patch is fed with the LD-alkyl-ester solution preferably by gravity, or alternatively by pump, the solution then being spread on the skin area covered by the patch. During treatment, the patient ingests tablets of carbidopa (25-50 mg/tablet) three times a day. According to the clinical needs, the patient could receive a supplemental treatment such as oral anti-parkinson""s drug.